This proposal's aim is to evaluate novel approaches for vaccination against herpes simplex virus (HSV). We hypothesize that immunization for the respiratory tract with DNA based vaccines or immunization enterically with replication incompetent recombinant HSV vectors can be tailored to produce different forms of immunity in the vaginal tract. If sufficient anti-HSV antibody of the appropriate type is induced, this may protect against viral invasion and so provide barrier immunity. However, clearance of virus from the invaded vaginal mucosa likely requires optimal CD4+ T cell function and perhaps CD8+ T cell responses. Vaccines will consist of combinations of plasmid DNA encoding the major glycoprotein gB along with DNA encoding one or more immunomodulatory molecules administered intranasally, or recombinant HSV vectors expressing immunomodulating proteins given enterically. The efficacy of vaccines at inducing various parameters of T cell and humoral immunity will be assessed. Animals will be challenged via the vaginal route HSV to measure protection and to establish the relationship of immunity to the activity of one or more immune components. In addition, vaccines will be tested for their ability to switch the pattern of immune responsiveness in animals primed to express CD4+ Th2 mediated responses and lacking CD8+ T cell reactivity. To achieve pattern shifting, DNA vaccines encoding viral protein along with oligonucleotides containing unmethylated CpG dinucleotides will be used. Our results should be applicable to the future design of vaccines against HSV and may have application to other situations that require immunomodulation.